Category Archives: Stem Cells

Dublin, Aug. 03, 2021 (GLOBE NEWSWIRE) -- The "Hematopoietic Stem Cell Transplantation (HSCT) Market - Size, Share, Outlook, and Opportunity Analysis, 2019 - 2027" report has been added to ResearchAndMarkets.com's offering.

Hematopoietic stem cell transplantation is a procedure in which multipotent hematopoietic stem cells sourced from peripheral blood cells, bone marrow, or umbilical cord blood are transplanted into the patient. Hematopoietic stem cell transplantation is commonly used in the treatment of lymphoma (Hodgkin, Non-Hodgkin), leukemia, multiple myeloma, thalassemia, sickle cell anemia, and osteoporosis. It includes two transplantation sources; 1) autologous, that uses stem cells from the patient's own body, 2) and allogeneic that sources stem cells from a donor's body. According to World Health Organization (WHO), over 50,000 hematopoietic stem cell transplantation procedures are carried out globally, every year and this number is expected to increase over the years.

Market Dynamics

The global hematopoietic stem cell transplantation market is expected to witness significant growth during the forecast period owing to the increasing prevalence of leukemia and lymphoma. According to Center for Disease Control and Prevention (CDC), in the U.S., around 45,360 people were diagnosed with leukemia in 2013, leading to 23,549 fatalities (13,625 men and 9,924 women). According to the same source the condition is more prevalent among men than women. Leukemia accounts for around 3% of all new cancer cases.

Key features of the study:

This report provides in-depth analysis of the global hematopoietic stem cell transplantation market, market size (US$ Mn), and compound annual growth rate (CAGR %) for the forecast period 2020-2027, considering 2019 as the base year

It elucidates potential revenue opportunity across different segments and explains attractive investment proposition matrix for this market

This study also provides key insights about market drivers, restraints, opportunities, new product launches or approval, market trends, regional outlook, and competitive strategies adopted by leading players

It profiles key players in the global hematopoietic stem cell transplantation market based on the following parameters - company overview, financial performance, product portfolio, geographical presence, distribution strategies, key developments, and strategies

Key players covered as a part of this study are Pluristem Therapeutics Inc., CellGenix GmbH, Regen Biopharma Inc., Lonza Group, Kiadis Pharma, Taiga Biotechnologies, Inc., Takeda Pharmaceutical Company Limited, Escape Therapeutics, Inc., Bluebird Bio, Talaris Therapeutics, Inc., Marker Therapeutics Inc., and Stempeutics Research Pvt Ltd.

Insights from this report would allow marketers and management authorities of companies to make informed decision with respect to future product launches, government initiatives, technological upgradation, market expansion, and marketing tactics

The global hematopoietic stem cell transplantation market report caters to various stakeholders in this industry, including investors, product manufacturers, distributors, and suppliers in the hematopoietic stem cell transplantation market, research and consulting firms, new entrants, and financial analysts.

Key Topics Covered:

1. Research Objectives and Assumptions

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2. Market Overview

3. Market Dynamics, Regulations, and Trends Analysis

Market Dynamics

Drivers

Restraints

Market Opportunities

Impact Analysis

Key Developments

Pipeline Analysis

PEST Analysis

Reimbursement Scenario

Regulatory Scenario

Epidemiology

Government Initiatives

Treatment Algorithm

4. Impact Analysis of COVID-19

5. Global Hematopoietic Stem Cell Transplantation (HSCT) Market, By Transplant Type, 2016 - 2027, (US$ Million)

Introduction

Market Share Analysis, 2020 and 2027 (%)

Y-o-Y Growth Analysis, 2017 - 2027

Segment Trends

Autologous

Introduction

Market Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Allogeneic

Introduction

Market Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

6. Global Hematopoietic Stem Cell Transplantation (HSCT) Market, By Indication, 2016 - 2027, (US$ Million)

Introduction

Market Share Analysis, 2020 and 2027 (%)

Y-o-Y Growth Analysis, 2017 - 2027

Segment Trends

Acute Myeloid Leukemia (AML)

Introduction

Market Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Acute Lymphoblastic Leukemia (ALL)

Introduction

Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Hodgkin lymphoma (HL)

Introduction

Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Non-Hodgkin Lymphoma (NHL)

Introduction

Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Multiple Myeloma (MM)

Introduction

Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Other Non-malignant Disorders

Introduction

Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

7. Global Hematopoietic Stem Cell Transplantation (HSCT) Market, By Application, 2016 - 2027, (US$ Million)

Introduction

Market Share Analysis, 2020 and 2027 (%)

Y-o-Y Growth Analysis, 2017 - 2027

Segment Trends

Bone Marrow Transplant (BMT)

Introduction

Market Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Peripheral Blood Stem Cells Transplant (PBSCT)

Introduction

Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

Cord Blood Transplant (CBT)

Introduction

Size and Forecast, and Y-o-Y Growth, 2016 - 2027, (US$ Million)

8. Global Hematopoietic Stem Cell Transplantation (HSCT) Market, By Region, 2016 - 2027, (US$ Million)

Introduction

Market Share Analysis, By Region, 2020 and 2027 (%)

Y-o-Y Growth Analysis, By Region, 2017 - 2027

Regional Trends

North America

Market Size and Forecast, By Transplant Type, 2016 - 2027, (US$ Million)

Market Size and Forecast, By Indication, 2016 - 2027, (US$ Million)

Market Size and Forecast, By Application, 2016 - 2027, (US$ Million)

Market Size and Forecast, By Country, 2016 - 2027, (US$ Million)

U.S.

Canada

Europe

Market Size and Forecast, By Transplant Type, 2016 - 2027, (US$ Million)

Market Size and Forecast, By Indication, 2016 - 2027, (US$ Million)

Market Size and Forecast, By Application, 2016 - 2027, (US$ Million)

Market Size and Forecast, By Country, 2016 - 2027, (US$ Million)

U.K.

Germany

Italy

France

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Insights on the Hematopoietic Stem Cell Transplantation Global Market to 2027 - Key Drivers, Restraints and Opportunities - Yahoo Finance

Whethers its the birth of a new space tourism industry or simply the ultimate game of one-upmanship it seems like a new billionaire blasts off every week.

So its worth keeping in mind that there are actually important things to study in space. In particular, theres vast potential for the kind of space-based manufacturing being studied by the University of Pittsburghs McGowan Institute for Regenerative Medicine, and the International Space Station National Laboratory, currently orbiting the Earth with scientists aboard.

The International Space Station Research and Development Conference 2021, which is taking place this week, includes a fireside chat with McGowan Institute Director William Wagner about the opportunities for biomanufacturing in space, particularly in the fields of tissue engineering and regenerative medicine. A preprint (not yet peer-reviewed) of their research was posted online this week.

So what is regenerative medicine, and why does it work well in space?

A definition that I like is that regenerative medicine involves harnessing the bodys ability to heal itself, says Wagner. That can include the use of stem cells or biomaterials and devices.

International Space Station. Photo courtesy of NASA.

Pittsburghs expertise in regenerative medicine can be traced back to Thomas Starzl.

Dr. Starzl made Pittsburgh ground zero for organ transplantation and revolutionized care for patients in end-stage organ failure, says Wagner. This built a group of experts in Pittsburgh interested in how to manage patients with failing organs. Transplant is an attractive option, but given that there are limited donors and there are delays in availability what about other approaches? This led to the development of the McGowan Institute, which initially focused on artificial organs (such as hearts), but broadened its mission to embrace regenerative medicine approaches.

The advantage of studying this in space is because of how microgravity in low Earth orbit favorably affects biology, including a higher reproduction rate of stem cells. The conference illuminated several opportunities for space-based biomanufacturing research and development.

Photo courtesy of the International Space Station Research and Development Conference.

Its a new space race, one that has vast implications for the future of medicine.

I personally believe that the future will find engineers and life scientists harnessing microgravity phenomena to develop medical products, says Wagner.

The McGowan Institute team in Pittsburgh has been working for two years to develop a roadmap for biomanufacturing in low Earth orbit.

The number of launches into orbit has increased dramatically over the past several years, costs have plummeted and private enterprise is making its own investments This capacity and cost reduction further opens up the ability for life science advancements, says Wagner.

International Space StationISSMcGowan Institute for Regenerative Medicinespaceuniversity of pittsburgh

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Pitt researchers partner with International Space Station on biomanufacturing - NEXTpittsburgh

GoodCell's FSA/HSA eligible product helps consumers improve healthcare outcomes & reduce medical costs

WALTHAM, Mass., Aug. 3, 2021 /PRNewswire/ -- GoodCell ("LifeVault Bio"), an FSA/HSA eligible member-based program offering genetic testing, health screenings and personal biobanking, added Navia Benefit Solutions, a national leader in consumer health insurance and benefits administration, to its growing affiliate network.

Navia plan participants now have access to GoodCell product and services which will help them to better understand their current health, track the progression & regression of major chronic diseases, understand future genetic predispositions, and bank their stem cells for potential future use.

"Our members are engaged in the decisions for their health and their families, and they want access to genetic information that is actionable, not just for their current lifestyle, but for the medical treatments that will be available as they age and even for their future generations," said Hilarie Aitken, Chief Executive Officer, Navia Benefit Solutions. "We chose to partner with GoodCell to give our members access to the most comprehensive genetic testing on the market."

"Innovative health administrators like Navia Benefit Solutions are realizing the value of empowering individuals with the information and tools to make decisions for the health of themselves and their families." said Trevor Perry, Founder and Chief Executive Officer, GoodCell. "With nearly 800 stem cell therapies in clinical trials and an anticipated 10-20 new FDA approved therapies a year by 2025*, GoodCell is the only solution available to consumers to bank their own stem cells for their future health."

To learn more about GoodCell and how to become a member, visit http://www.GoodCell.com. To inquire about our affiliate partnership program, visit http://www.goodcell.com/affiliates.

About GoodCell

GoodCell empowers individuals to live longer and healthier lives with a medically actionable service that identifies, tracks and helps mitigate health risks. Driven by mounting evidence in support of cellular therapy, the company offers the only holistic solution that taps genetic and biological information as well as banked stem cells for potential use in the future. Committed to shaping the future of personalized health as today's science becomes tomorrow's medicine, GoodCell is led by a founding team of science and technology innovators with a diverse set of medical research. Learn more at: http://www.goodcell.com.

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About Navia Benefits Solutions

Navia is a national, consumer-directed benefits provider serving 7,000+ employers across all 50 states. The company provides comprehensive health and compliance solutions to employers and consumers, and offers industry-leading customer service, communications, and technology. Founded in 1989, Navia began as Flex-Plan Services, and over the years has grown into one of the nation's premier benefit providers. Navia offers FSA, HSA, HRA, Commuter, Wellness, and COBRA administration. http://www.naviabenefits.com

Cision

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GoodCell Adds Navia Benefit Solutions to its Affiliate Partnership Network Expanding Targeted Reach for its Direct-to-Consumer Healthcare Services -...

Marcela Iglesias, 43, who lives in Los Angeles, US, has spent 60,000 on cosmetic procedures to look like the popular toy doll but claims she has never had plastic surgery

A mum who has shelled out thousands so she can look like Barbie has revealed she wants to make an army of clones.

Marcela Iglesias, 43, who lives in Los Angeles, US, has spent 60,000 on cosmetic procedures to look like the popular toy doll but claims she has never had plastic surgery.

The mum-of-one has recently learned of human cloning and claims that not only are scientists currently working on this but by cloning herself, she could potentially help save lives by donating organs.

Marcela stumbled across the topic through Professor Nakauchi from the University of Tokyo, who has been conducting research into growing organs based on a patients stem cells.

She believes that cloning is already happening but that the general public just doesn't know about it yet.

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And the model is determined to have her very own army of Barbies, so that she can donate her organs to those who need them.

"I want to be cloned and then see if we can use those organs for donation or for myself In the future," Marcela said.

"An army of clones to use for a good cause would be great. There are far more patients requiring organ transplants than organ donations.

"By donating my stem cells and some of my eggs, they can be used to create human organs in order to help people that need the transplant."

Marcela has a personal connection to the topic, having lost her father, who needed a kidney transplant.

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Since his death, she has had 30 million stem cells transplanted into her bloodstream from an umbilical cord.

She said: "If I had a kidney for my father, he would be alive today and the fact that I have 30 million more stem cells that were injected into my body means that I can help with that research.

"I started the research of stem cell therapy because of my fathers diseases and I have learned a lot about it.

"Unfortunately, my dad passed and he didnt want to go through the treatment, so I took the advantage of all the information and I decided that it was time for me to do it.

"After all the information I gathered, I decided that mesenchymal stem cells via IV therapy was the one for me, there are many other procedures, but this was the most convenient."

Image:

She had the procedure done in the US for around $6,000 (USD) and according to Marcela, it was successful and she believes it will boost her immune system.

The model said: "The treatment went great; its like receiving IV fluid, I was there for an hour and a half and I felt very relaxed.

"The doctor showed me the three tubes where the 30 million stem cells arrived, they were frozen.

"The treatment is not cheap but I feel that people, in general, including myself, spend a lot of money on things that have no benefit in the long term, especially when it comes to health, so I decided to dig into my savings and give my body a great gift."

The model is currently trying to get in touch with Professor Nakauchi so that she can discuss making her clones.

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Mum who spent 60,000 turning into a real life Barbie wants 'army of clones' - The Mirror

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Medexus Pharmaceuticals and medacGmbHreceiveda Complete Response Letter (CRL) from the Food and Drug Administration (FDA) for its New Drug Application (NDA) for treosulfan. The drug was being submitted for use in combination with fludarabine as a preparation for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The companies had a target action date of August 11.

A preparative regimen is given to the patient before stem cell transplantation with the goal of decreasing the tumor burden. And in the case of allogeneic transplantation, it allows for engraftment of the donor cells.

The CRL indicated that it couldn't be approved in its present form. It offered specific recommendations, including additional clinical and statistical data related to the primary and secondary endpoints of the pivotal Phase III trial. The companies say they are reviewing the CRL to decide on a course of action.

Ken d'Entremont, chief executive officer of Medexus, said, "Given the recent Health Canada approval, European Medicines Agency approval in 2019, as well as supporting data from more than 100 publications, we were all surprised by the FDA's response."

"That being said, Medexus and medac look forward to continuing to work with the FDA to address their requests in a timely manner, and we remain optimistic for a future, albeit delayed, approval of treosulfan in the United States, complete with Orphan Drug Designation."

He went on to say that the current standard of care "is not suitable for numerous at-risk groups, due to the high toxicity effects, and treosulfan has demonstrated excellent survival data among those groups."

Medexus, headquartered in Toronto, Ontario, Canada, and medac, based in Wedel, Germany,inkeda licensing deal on July 12 to commercialize treosulfan in Canada. It is being marketed in Canada under the name Trecondyv. Medexus will handle sales and marketing, while medac will handle manufacturing and supply.

The therapy has been distributed in Canada under the Special Access Program and recently received approval for commercialization from Health Canada for adults with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) who are at increased risk for standard conditioning therapies. It was also approved for children older than one-year-old with AML or MDS.

At the time, Magnus Kuster, vice president of International Sales & Regions for medac, noted, "The treosulfan-based conditioning regimen stands out for its combination of being highly effective similar to the potency of myeloablative procedures while simultaneously exhibiting significantly reduced toxicity. We at medac are very proud of our first-in-class conditioning agent as it fully meets our company's goals of improving patients' lives and supporting healthcare professionals in the best possible way."

In response to the CRL, Meduxus's general manager of U.S. Operations, Michael Adelman, said, "We are disappointed with the immediate result, but are encouraged by an incredible amount of support from key opinion leaders and the medical community for use of treosulfan in the United States. With the extensive launch preparations we have taken to date, we are well positioned to meet the expected strong demand for treosulfan."

They will work with the FDA to address the issues in the CRL while ready to trigger their U.S. marketing plan when it gets approved.

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FDA Hands Out Surprising Rejection of Meduxus and Medac's Treosulfan - BioSpace

4 min read30 July

Taking account of a patients background, the circumstances of their lives and the particular challenges they might face is crucial to delivering complex treatments like stem cell transplantation.

In May, the APPG on Stem Cell Transplantation published a report following its inquiry looking at how a patients background and circumstances, including a patients geographical location, socioeconomic background and ethnicity, can lead to barriers when accessing treatment and care.

Health Inequalities, as defined by NHS England, are unfair and avoidable differences in health across the population, and between different groups within society.

Rik Basra discovered the difficulties faced by patients of an Asian background when his Acute Myeloid Leukaemia (AML) returned after a two-year remission. The only hope for Rik was a stem cell transplant but he discovered his would be an uphill battle because its less likely for patients of an ethnic minority background to have someone already on the stem cell donor register who is a genetic match to donate their stem cells for this lifesaving treatment. Unfortunately for a variety of reasons, ethnic minority patients have only a 37% chance of finding an unrelated stem cell donor, compared to 72% for white patients.

This is just one of the experiences we heard about as part of this important Inquiry. A patient shouldnt experience disparity when it comes to the best treatment and care or chance of survival and future quality of life because of their background. The inquiry has explored how ethnicity, as well as other factors such as age, where you live and your socio-economic status can impact different parts of a patients treatment and care journey when receiving a stem cell transplant. The focus has been on understanding where the barriers lie, and what can be done to remove these barriers.

We were fortunate that we were able to find a donor for Max, others were not so lucky, particularly those from mixed race and ethnic minority backgrounds

My interest in this area stems from personal experience when some 13 years ago my elder son Max was diagnosed with Leukaemia. This was devastating for my son and my family. The whole world turns upside down as you embark on a programme of treatment and the subsequent decision to go down the transplant path.

We were fortunate that we were able to find a donor for Max. We were acutely aware that others were not so lucky, particularly those from mixed race and ethnic minority backgrounds. We were again fortunate that we had a supportive family network and a job that paid well. For many the financial impact of supporting a family member through this journey is huge and rarely talked about. I have long argued that we need to look at a treatment and support plan that looks at all these factors rather than just the physical treatment itself.

We received rich and insightful responses in our inquiry from over 40 patients, family members, clinicians, charities, and researchers through written and oral evidence. What became clear was that taking account of a patients background, the circumstances of their lives and the particular challenges they might face is crucial to delivering complex treatments like stem cell transplantation.

Our report explores recommendations to address these challenges, calling on government and the NHS, amongst others, to make changes such as investing in research and making sure care is culturally appropriate, meaning healthcare professionals have the ability to understand, communicate with and effectively interact with people across cultures. We were joined by Lord Bethell, a Health Minister with responsibility for stem cell transplantation, at the report launch. He commented on timeliness of this report and welcomed the recommendations made, citing a commitment for the Department to work with APPG on the recommendations.

We hope the findings from this report will act as a springboard to encourage more research and a renewed focus on understanding and overcoming barriers to accessing treatment and care for a stem cell transplant.

Our findings and our recommendations will be relevant far beyond stem cell transplantation. Its vital we use the lessons from the pandemic to make a real step-change in health inequalities. We have a once in a lifetime opportunity to ensure patients get the treatment, care and support they need whatever their background. Find out more about the inquiry here.

Mark Tamiis the Labour MP for Alyn and Deeside and chair of theAPPG on Stem Cell Transplantation.

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Background should not be a barrier to access stem cell transplant treatment and care - PoliticsHome

While blood cancer is not top of mind when it comes to fatal cancers, it is one of the top five cancers affecting people globally. This is according to Dr Estelle Verburgh, clinical haematologist and associate professor in Clinical Haematology at the University of Cape Town, who adds that often the only hope for a cure is a blood stem cell transplantation.

In a bid to raise funds and awareness for those who are suffering from blood disorders and cancers, DKMS Africa (formerly known as the Sunflower Fund) will once again embark on their annual Sunflower Day campaign which will be celebrated on the 17th of September 2021. This special day is usually honoured through the sale of the Tube of Hope (TOPE) and this year is no different with topes going on sale from August 2021.

Alana James, Country Executive Director at DKMS Africa, says that hope is a fundamental need for those suffering from life-threatening illnesses such as blood disorders and cancers, and in some instances, hope is all that a patient has.

It is for this very reason that the 2021 instalment of the Sunflower Day is dedicated to celebrating the power of hope, she says. At DKMS Africa, we believe that hope is the one underlying attribute that can get anyone through the darkest of times, and for many patients battling a blood-related illness, hope can come in the form of a second chance at life through blood stem cell donations.

James adds that while the purpose of Sunflower Day is to create awareness and raise funds, its also an important platform to create awareness and drive the conversation around stem cell transplantations and the associated misconceptions.

As the bodys primary cells, all cells such as bodily tissue, organs and bones develop from it. The stem cells which are found in the bodys bone marrow are responsible for creating the various types of blood cells, all with a unique job to do to keep our blood healthy. Registering to donate blood stem cells involves three DNA swabs collected from the inside of the mouth and cheeks, and can be done from the comfort of a potential donors home.

Should a candidate be a match, they will be contacted to donate. The procedure is non-invasive and painless and does not require an operation, anaesthetic or incisions. The procedure involved travelling to a collection centre to have a full medical assessment to assess the donors suitability to donate. Donors are then required to provide a blood sample which will be confirmed as an HLA match and screened for infectious disease markers. 30 days after the examination blood stem cells are then collected from the donor. The process is completely free and donors only donate blood stem cells twice in their lives.

By donating blood stem cells, everyday people become the hope patients with blood disorders and cancers need to beat their illnesses, and we urge the public to drive the conversation around the importance and need for blood stem cell transplants, says James.

With the tribulations of 2020 and this year, DKMS Africa implores South Africans to embody the idea of hope. By purchasing a TOPE for as little as R30 from Pick n Pay stores, selected ICPA pharmacies and online at Zando. The TOPE is available in six eye-catching unisex colours including blue, green, yellow, pink, red and black.

With all proceeds assisting the DKMS Africa to recruit blood stem cell donors and contribute to the growth of the patient assistance fund, its one way, apart from being a blood stem cell donor, that the public can be a beacon of hope for many, concludes James.

Should you be interested in becoming a donor, between the ages of 18-55 and in general good health, register to become a stem cell donor today. For more information visit DKMS-Africa.org or to register visit or call 0800 12 10 82.

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Support Blood Cancer Patients This Sunflower Day; DKMS's Africa's Tube of Hope (TOPE) Are Officially On Sale! iAfrica - iAfrica.com

A mum-of-three and the hospital chaplain she befriended when she received a bone marrow transplant two years ago have enjoyed a tearful reunion after discovering he was the donor who saved her life.

Clergyman Mario Sant, 39, is one of two hospital chaplains stationed in London as part of a joint venture by the Maltese government and the Catholic Church to support patients sent to the UK for procedures which cannot be performed on the tiny island.

Taking the position six years ago, Maltese national Mario was moved by the plight of a five-year-old boy who needed the same transplant at the famous Great Ormond Street Hospital in 2018 to become a bone marrow donor.

A chaplain based in the UK, Mario was moved by a brave boy to donate stem cells (Collect/PA Real Life).

Sadly, he was too late to help the boy, who died a few months later, but he joined the international database DKMS as a bone marrow donor in December 2018.

In the meantime, he met leukaemia patient Agnes Vella, 59, a mum of three from Malta, in March 2019, who needed stem cells from bone marrow to stop her cancer from returning and they bonded, according to Mario, who said: We got on immediately.

She was at the Royal Marsden in London, and we joked that I could be her donor, as I was called to donate as she arrived.

He added: But her records said the donor was English and I was born in Malta, so we didnt think it was me.

Plus, I donated at a different hospital, so it just didnt fit. I think we both hoped and joked about it, but we thought it wasnt possible.

Neither Mario nor Agnes, a housewife, whose husband Francis, 65, is a retired freight worker, gave it a second thought although their friendship blossomed, and they stayed in touch.

Mario has been living in London for six years (Collect/PA Real Life).

Then, in May 2020, when she felt compelled to thank the donor who had saved her life emailing the DKMS asking if she could contact the stranger that helped her she and Mario were in for a gigantic surprise.

Records revealed that Agnes guardian angel was in fact the hospital chaplain who had become her friend.

It was amazing to discover that I was Agnes donor, said Mario.

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He added: The work I do is very special. We are there for people during their joy and sadness.

When Agnes called saying she had asked for the details to be released and I got the email instantly asking if I wanted to give the woman I donated to my details, it all added up.

It was amazing, from that moment we knew I was her donor. We just couldnt believe that we had unwittingly shared such a special journey together.

Mario with Agnes on the day of her transplant in March 2018 (Collect/PA Real Life).

Meanwhile, Mario, who has been living in London and supporting Maltese patients for six years, says the amazing news is a poignant reminder of the little boy who inspired him to donate.

He said: Sadly, he had leukaemia and he didnt make it, but its all thanks to this child that I donated.

I spent a lot of time with him and his family at Great Ormond Street.

He added: He was so brave. He needed another bone marrow transplant, but they were struggling to find a match.

I just thought to myself, Why dont I donate? So, I registered, but I didnt realise it can take nine to 10 months to become a bone marrow donor.

I couldnt help the child, but I could help others.

Agnes Vella with her husband Francis, and three children (Collect/PA Real Life).

And, three months after signing up to DKMS, an international non-profit bone marrow donor centre, he was called to donate.

He said: Over that time, I continued working and helping other patients and thats how I met Agnes.

I love my job. London is one of the nicest cities Ive lived in and the work I do is very special.

90% of stem cell cases are taken from the bloodstream

At any one time there are around 2,000 people in the UK in need of a blood stem cell transplant

By January 2021 two million people had registered to be blood stem cell donors in the UK

He added: Maltese patients come over for treatment and so, as a religious state, the government provides two chaplains to help them through their treatment.

For a lot of patients were the only family they have during some dark times, so its really special to be part of it.

For Agnes, who was in remission from leukaemia after previously surviving two bouts of breast cancer, the bone marrow transplant was essential to stop her disease from returning within a year.

Agnes and Francis Vella (Collect/PA Real Life).

And Mario, who donated his own stem cells at Londons Kings College Hospital the day before her op, was there to hold her hand as she was prepared for the procedure at the Royal Marsden.

The transplant was a success and four months later, Agnes returned home to Malta.

But the friends stayed in touch, chatting by phone every week.

And when they discovered he was her donor, their thoughts immediately went to arranging a reunion as soon as Covid travel restrictions allowed it.

So, on July 31, they finally got to have the hug of a lifetime, when they met for the first time since her transplant, at Agnes home in Malta.

I was so excited to see Agnes, said Mario.

We hadnt been able to meet since we found out because of the pandemic. We chat all the time, but we wanted to meet in person.

We laugh that we must be related now, because I was a match. Its crazy to think that in an international database two people from such a small island could be a match.

Im just so grateful shes healthy.

While Agnes was ecstatic to meet up with not just her friend, but the donor who saved her life.

She said: I met Mario when I went to London for treatment. We met every day. He would even come by at weekends and we would have dinner together or a little party with the other patients.

It was really special. We became like a little family.

Mario and Agnes reunited August 2021 (Collect/PA Real Life).

She added: The staff at the Royal Marsden and at the Sir Anthony Mamo oncology centre, where I was on the haematology ward, in Malta took such good care of me, too Im so grateful to them.

When I arrived in London, Mario told me he had been called to donate. But we never thought it would be for me. I was told my donor was English, and though Mario lives in England, hes Maltese, so we felt sure it couldnt be him.

And she is keen for the lifesaving DKMS register, which also operates in Germany, India, Chile, Poland, Africa and the United States to operate in Malta too.

She said: My family wanted to register but they cant as they dont have UK addresses that was why Mario was able to donate.

He saved my life, Im so thankful to him.

MUST PAR: Taking the first steps to register as a potential blood stem cell donor can be done from the comfort of your own home. If you are aged between 17-55 and in good health you can sign up for a home swab kit online at https://www.dkms.org.uk/register-now. Your swabs can then be returned with the enclosed pre-paid envelope to DKMS in order to ensure that your details are added to the UKs aligned stem cell register. [END]

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CAMBRIDGE, Mass., August 03, 2021--(BUSINESS WIRE)--Cellino, a personalized regenerative medicine company developing an AI-guided laser editing platform for autologous cell-based therapies, today announced the appointment of industry pioneer Robert J. Palay, J.D., M.B.A., to the Cellino Board of Directors.

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Robert J. Palay (Photo: Business Wire)

Mr. Palay is one of the pioneers of the induced pluripotent stem cell (iPSC) industry. He was Founder, Chairman of the Board, and Chief Executive Officer of Cellular Dynamic International (NASDAQ: ICEL), one of the first companies to harness IPSCs and their derivatives for use in drug discovery and therapeutics. CDI was acquired by FujiFilm for $307M in 2015. Prior to Cellular Dynamic International, he was a co-founder and Chairman of the Board of NimbleGen Systems, a early adopter of light directed synthesis for manufacturing genomic micro-arrays. NGS was acquired by Roche in 2007 for $272.5M. He was previously a Fellow at Harvards Advanced Leadership Initiative where he focused on emerging biothreats.

"We are pleased to welcome Robert to the Cellino Board," said Nabiha Saklayen, Ph.D, CEO & Co-Founder, Cellino. "Roberts deep experience in pioneering the light-directed synthesis and iPSC industries will be invaluable to Cellino as we grow our business at that unique interface and pursue our mission to serve patients."

"I am thrilled to join the Cellino Board," said Robert J. Palay. "Cellinos platform is the future of the stem cell industry. They have the unique ability to bring laser precision and artificial intelligence to the manufacture of IPSCs and their derivative cells. Their innovation offers a clear path to dramatic improvements in the quality and quantity of manufactured human cells, while simultaneously dramatically reducing cost. No one else has technology offering such a robust and powerful platform."

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Mr. Palay was also a co-founder and Chairman of the Board of Genetic Assemblies, a synthetic biology company, which was acquired by Codon Devices in 2006. Mr. Palay is currently Chairman of Tactics II Equity LLC, a life science investment and advisory firm. He is currently a member of the board of directors of the Center for Strategic Risks and a founder of the Alliance to End Biological Threats. Mr. Palay received a J.D. and M.B.A. from Northwestern University, and an A.B. from Harvard College.

About Cellino

Cellino is an autologous regenerative medicine company developing an AI-guided single-cell laser editing platform for cell-based therapies. The company has developed a scalable platform that automates and standardizes autologous stem cell production, accelerating the development of life-saving medicines for patients. Cellino is based in Cambridge, MA. For additional information, please visit http://www.cellinobio.com.

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Contacts

Kimberly HaKKH Advisors917-291-5744kimberly.ha@kkhadvisors.com

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Introduction

Traumatic brain injury is a leading global cause of mortality and morbidity and the main cause of death in young people living in industrialized countries.1,2 Traumatic brain injury is mainly caused by an external mechanical force causing brain trauma. Traumatic brain injury and the ensuing neuroinflammation, in addition to causing motor and cognitive deficits, may persist long after the initial injury.3 Furthermore, long-term neuroinflammation has been related to increased risk of neurodegenerative disorders and various other deficits.4 Traumatic brain injury as a risk factor for brain tumors has been a controversial topic in medicine for over a century.58 However, as statistical reports on brain tumors often exclude post-traumatic glioma, relevant information on the incidence of gliomas caused by traumatic brain injuries is rare. Although previous clinical studies and case reports are often vague and difficult to evaluate since most of them were published so many years ago,512 some are quite striking, such as the cohort study by Munch et al5 in which the reduced long-term risk of malignant astrocytic tumors after structural brain injury was evaluated. However, this study was conducted using a small population. Furthermore, it is to be noted that traumatic brain injury is only one type of structural brain injury in this study. Additionally, it is challenging to confirm the incidence of post-traumatic glioma owing to the frequently considerable time gap between traumatic brain injury and glioma. Thus, there is an urgent need to systematically evaluate the role and outcome of head trauma in the incidence and progression of glioma. In this review, our primary focus is to document the interrelationship between traumatic brain injury and glioma based on a comprehensive review of the existing literature, which is discussed in detail. First, we present an overview of previous cohort studies and various case reports regarding the relationship between traumatic brain injury and glioma. Next, we discuss the roles of microglial cells, macrophages, astrocytes, and stem cells in post-traumatic glioma formation and development. Moreover, we also briefly discuss the various carcinogenic factors during traumatic brain injury that could explain the interplay between these two parameters. We have also summarized the common inflammatory and oxidative stress-related signaling pathways related to traumatic brain injury and glioma. Lastly, we have elaborated on the strategy that could be considered in a clinical setting, and have concluded this review with directions for future research.

All previously published cohort studies and case-control studies are not directly comparable owing to differences in exposures and outcomes (Table 1). A population-based study by Inskip et al8 reveals an increased overall incidence of intracranial tumors of head trauma patients, whereas no significant association was found in the case of malignant astrocytic tumors. In a cohort study by Nygren et al7 no significant association between traumatic brain injuries and brain tumors was identified; moreover, specific risks for malignant astrocytic tumors were not reported. However more recently, a cohort study by Chen et al6 indicated an increased risk for not otherwise specified malignant brain tumors within 3 years after a traumatic brain injury. Besides, interestingly, a research group demonstrated a decreased risk 5 or more years after structural brain injury; however, they did not find convincing evidence for an association between structural brain injury and malignant astrocytic tumors within the first 5 years of follow-up.5 The authors speculated that the inflammatory response after traumatic injury could cause elevated immunological alertness for astrocytes undergoing neoplastic transformation, as well as a clearance of premalignant astrocytes or neural stem cells, which may otherwise have developed into glioma. Although their study demonstrated that structural brain injury may generally reduce the long-term risk of malignant astrocytic tumors, their data also supported that structural brain injury specifically caused by trauma (different from other types of exposures such as cerebral ischemic infarction and intracerebral hemorrhage) could increase the long-term risk of malignant astrocytic tumors. Thus, the relationship between traumatic brain injury and glioma is still not conclusive and warrants further studies.

Table 1 Overview of Published Epidemiological Studies Exploring the Causal Relationship Between Traumatic Brain Injury and Glioma

It is often a challenge to compare the results of previously published epidemiological studies,58 as it involves individuals of different ages who live in different environments. Importantly, most studies have also not been standardized regarding the type or the severity of brain damage. The low incidence of brain tumors also hinders the design of relevant research. There is currently an urgent need for more comprehensive and larger-scale epidemiological investigations, including cohort studies and case-control studies, to evaluate post-traumatic glioma. To date, very few case-control studies have specifically reported the risk for malignant astrocytoma/glioma after traumatic brain injury, and conclusively, the currently available findings are equivocal with null9,10 or positive associations.11,12 For the first time, Hochberg et al12 have done a case-control study of 160 persons with glioblastoma, and the results suggested that severe head trauma in adults is a significant risk factor for glioblastoma. After that, Zampieri et al12 did another case-control study to find potential risk factors for cerebral glioma in adults, however, their study yielded no meaningful association between head trauma and glioma. Besides, the case-control study done by Preston-Martin et al10 investigated the role of head trauma from injury in adult brain tumor risk. Although not significant association between head trauma and glioma has been found, their findings suggest that an association between head trauma and brain tumor risk cannot be ruled out and should therefore be further studied, and future studies of head trauma and brain tumor risk should consider potential initiators of carcinogenesis, such as nitrite from cured meats, as modifiers of the trauma effect on risk of brain tumor. Furthermore, Hu et al11 also exerted case-control study of risk factors for glioma in adults, interestingly positive associations between brain trauma and glioma has been found. Unfortunately, all case-control studies were conducted before the year 1998, and no newly published research worthy of reference could be found suitable for discussion in this review. The advantages of cohort studies have been highlighted in various studies; therefore, most researchers give more weightage to cohort studies than case-control studies when systematically evaluating evidence.13,14 Thus, additional more cohort investigations with correct and standardized study designs are much needed to gain a better understanding of post-traumatic glioma.

The results of the published epidemiological studies could not be compared uncritically, as the types of brain injuries differed, and patients belonged to different ethnic groups and different ages. Difficulties in conducting epidemiological studies can be attributed to the low incidence of brain tumors. More efforts should be directed toward investigating the causal relationship between traumatic brain injury and glioma, which is supported by several published case reports.1527 Although these reports from epidemiological observations have not conclusively confirmed the relationship between traumatic brain injury and glioma,58 some reports discuss the follow-up details of patients in great detail and are indicative of the possibility of such a relationship.1527 Anselmi et al15 reported two cases of brain glioma that developed in the scar of an old brain trauma, these two cases fulfill the established criteria for a traumatic origin of brain tumors and add further support to the relationship between cranial trauma and the onset of glioma. Di Trapani et al16 reported that several years after sustaining a commotive left parietal trauma, one patient developed a mixed glioma in the left temporo-parietal-occipital region in continuity with the scar resulting from the trauma. Magnavita et al17 reported the case of a patient who suffered a severe head injury to the right temporoparietal lobe, and the patient developed a glioblastoma multiforme at the precise site of the meningocerebral scar 4 years later. Moorthy et al18 reported a case of a 56-year-old man who had history of head injury 5 years prior with CT evidence of bilateral basifrontal contusions. Imaging showed a large left frontal intra-axial mass lesion and the histopathology was reported as glioblastoma multiforme. The authors formulated additional radiologic criteria for tumors that may present following trauma. Mrowka et al19 reported that a glioblastoma multiforme developed 30 years after a penetrating craniocerebral injury in the left parietal region caused by fragments of an artillery projectile. Sabel et al20 reported that a patient developed a left-sided frontal glioblastoma multiforme at the precise site of the meningocerebral scar and posttraumatic defect 37 years later. Witzmann et al21 reported a case of a 28-year-old male who suffered a frontal penetrating gunshot injury with subsequent bifrontal brain abscess and subdural empyema, and five years later developed a large bifrontal glioblastoma multiforme at the precise site of the meningo-cerebral scar and posttraumatic defect. Zhou et al22 also reported one case of glioblastoma multiforme that developed in the scar of an old brain trauma 10 years ago. Han et al23 presented the first case of pregnancy-related post-traumatic malignant glioma in a 29-year-old female, and suggested that pregnancy may promote the manifestation of the clinical symptoms. Tyagi et al24 used radiographic evidence from two patients to assess the possibility of a link between TBI and glioblastoma multiforme. Salvati et al25 presented 4 cases of post-traumatic glioma with radiological evidence of absence of tumor at the time of the injury. Henry et al26 reported a case of post-traumatic malignant glioma with radiological evidence of only a contusion prior to the development of the glioma. Simiska et al27 reported one case of post-traumatic glioma 2 years after head injury. Overall, some data from these studies might support the conclusion that the association is almost weak, while others not; but a causal relationship between traumatic brain injury and glioma is highly possible. This is because traumatic brain injury initiates inflammation, oxidative stress, repair, oncogene activation, and other pathophysiological changes, which are bound to lead to malignancy in at least some patients.28,29

Besides, to better identify reported cases addressing the relationship between traumatic brain injury and the incidence and development of glioma, an important aspect is to be able to recognize and differentiate between a tumor, traumatic brain injury-induced glioma, and post-traumatic glioma. We believe that only specific cases that fulfill certain conditions or criteria, could add to revealing the etiological association between head trauma and glioma. Thus, more efforts should be directed in establishing if there is a relationship between traumatic brain injury and gliomas, as well as diagnosing post-traumatic glioma. Since traumatic incidents are much more frequent than a possibly related tumor, James Ewing30 defined five criteria that could aid in the identification of post-traumatic glioma that could contribute to establishing the relationship between brain injury and the subsequent glioma. Subsequently, Zulch and Manuelidis31 revised Ewings criteria while adding their viewpoints. And Moorthy and Rajshekhar32 further added imaging-related screening criteria to this list. We believe that specific cases that fulfill these criteria, as well as possibly other cases with accurate retrospective data of traumatic brain injury and high risk of developing glioma, could add to the clarification of the etiological association between traumatic brain injury and glioma.

Neuroinflammation accompanying the activation of microglial cells and other effector cells has been suggested as an important mechanism of TBI.33 Active microglial cells can transform to the M1 phenotype, to secrete proinflammatory or cytotoxic mediators that mediate post-TBI cell death and neuronal dysfunction, or to the M2 phenotype, to participate in phagocytosis and secrete anti-inflammatory cytokines and neurotrophic factors that are important for neural protection and repair.34 Indeed, they can become polarized ranging from the classic M1 phenotype to an alternative M2 phenotype after TBI.35 The M1 response is presumed to be pro-inflammatory,36 whereas the M2 phenotype owns anti-inflammatory effects.37 Multiple molecular pathways, such as STAT, nuclear factor-B (NF-B), and interferon regulatory factor (IRF), are involved in the regulation of M1/M2 phenotypic transitions.3840 Preclinical evidence indicated that mixed phenotypes are present in the pathological processes of TBI, which offer opportunities for therapeutic interventions.41

Several mechanisms have been shown to be associated with the formation of post-traumatic glioma, specifically, inflammatory processes and oxidative stress, both of which are mainly involved in the removal of damaged components from the brain and are known to play irreplaceable roles in this process.24 In the brain, these mechanisms are mainly mediated by the microglia or other cells of the immune system.24,42 Microglia in the brain play a role in phagocytosis and antigen presentation, leading to the release of chemokines or cytokines.43 Interestingly, recent in vivo studies have shown that microglia could have different effects on the development of brain glioma, and also result in immunosuppressive conditions that promote glioma development.44,45 Although the growth-promoting effect of glioma by microglia after traumatic brain injury is controversial, its significant role in promoting an environment that can facilitate glioma development has been identified.43 Microglia can produce metalloproteinases in the tissues adjacent to glioma, which can facilitate tumor invasion.44 Besides, PGE2 can also contribute to the creation of an environment that facilitates glioma development.46 PGE2 is released by the microglia accompanying the developing glioma and can suppress T lymphocytes. The net effect is a decreased expression of major histocompatibility complex (MHC) class II molecules on antigen-presenting cells.46 Brain-repair processes mainly involve the microglia in normal conditions; however, during traumatic brain injury, various other cells from the immune system can also enter the brain parenchyma along with blood. These effects cannot be ignored.

Oxidative stress caused by ROS in the acute phase of TBI and cerebral infarction is thought to be detrimental, and macrophages have been recognized as the main cells that produce ROS.47 During traumatic brain injury, macrophages migrate to the site of the damaged blood-brain barrier and secrete interleukin 6 (IL-6). In normal conditions, the expression of IL-6 is very low, whereas, during traumatic brain injury, its production increases considerably.48 Brain injury elevates IL-6 production in both serum and CSF to high concentration. Notably, multiple TBI patients samples have also showed that the combination of elevated IL-6 concentrations is correlated with better outcomes in patients with TBI, suggesting IL-6 as a new therapeutic strategy as well as for prediction of disease outcome of patients with TBI.49 Importantly, high levels of IL-6 in the brain generally result in an adverse impact on microcirculation and lead to the destruction of the blood-brain barrier in an obviously wider area compared to the initial area of trauma.27 Thus, in traumatic brain injuries, it is crucial that the blood-brain barrier is not initially compromised, as IL-6 can subsequently promote the entry of macrophages to the site of injury and aggravate brain edema.24,42 Besides, Xu et al reported that IL-6 also impacts cell-cycle regulation42 and activates signal transducer and activator of transcription-3 (STAT3), which is important for cell proliferation, differentiation, and apoptosis. Previous studies show that STAT3 inhibition suppresses the growth of glioma cells and promotes apoptosis.43 These findings have also been confirmed in other in vivo studies.50,51 Besides, STAT3 activation can inhibit T lymphocytes and MHC II molecules on microglial and other antigen-presenting cells.43 Thus, STAT3 has an immunosuppressive effect and is likely a carcinogenic factor for glioma. Importantly, the increased concentrations of IL-6 and its receptors in the cerebrospinal fluid of patients who underwent traumatic brain injury are indicative of the involvement of IL-6 in glioma progression.42,43

The neuronal stem cells in the brain are mainly generated from the subgranular zone of the hippocampal dentate gyrus and the subependymal zones of the lateral ventricles.24 Traumatic brain injury leads to the migration of neuronal stem cells to the damaged sites to promote regeneration, thereby differentiating into astrocytes, neurons, and oligodendrocytes. Additionally, neuronal stem cells could release cytokines and neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF).24 Thus neuronal stem cells may be an effective treatment for neurological recovery after TBI.52 Interestingly, neuronal stem cells show a high expression of oncogenic genes and high sensitivity to chemical mutagenic factors.24 This is important because stem cells are involved in the production of ROS and various pro-inflammatory factors.24 Neuronal stem cells can be highly sensitive to mutagenic agents and could, thus, be easily mutated as a result of the action of certain agents. These characteristics may promote the formation of rapidly proliferating tumor cells and increase the progression of glioma in the brain.24,53 Migration of stem cells has already been identified in cases of traumatic brain injury, ischemia, and demyelination. However, there is a much higher risk of increased neoplastic transformation only during traumatic brain injury.24 Therefore, it is reasonable to accept the causal relationship between traumatic brain injury that induces brain stem cell activity and subsequent development of glioma.24 Stem cells have been generally recognized as potentially oncogenic in glioma54 and several studies have demonstrated their important role in the formation of gliomas.5557 The role of stem cells should be emphasized in the analysis of relevant mechanisms leading to glioma development induced by traumatic brain injury.

Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI.58,59 Increased reactive astrocytes and astrocyte-derived factors are generally observed in both experimental animal models and TBI patients.60 Astrocytes have beneficial and detrimental effects on TBI, including acceleration and suppression of neuroinflammation, promotion and restriction of neurogenesis and synaptogenesis, and disruption and repair of the BBB through various bioactive factors.61 Additionally, astrocytic aquaporin-4 is also involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI.

Based on case reports studying glioblastomas, neoplastic transformation of damaged astrocytes has been proposed as a possible mechanism occurring at the site of traumatic brain injuries.1527 Besides, it is generally accepted that astrocytes are essential components of the blood-brain barrier, and damage to the blood-brain barrier often occurs after the action of pro-inflammatory prostaglandins and leukotrienes, which triggers the effect of the relaxing of tight junctions.54 The pro-inflammatory factors lead to a relaxation of the capillary epithelium and the glial cells are exposed to potentially mutagenic agents.62 Traumatic brain injury accompanied by damage to the blood-brain barrier always causes a recovery reaction, which explains the recurrence of glioma in some cases.

To conclude, the summary of various carcinogenic factors that play a role during traumatic brain injury is presented in Figure 1. Traumatic brain injury can lead to the influx of macrophages to the site of brain injury, where they are activated and produce IL-6. Traumatic brain injury also induces enhanced IL-6 secretion by astrocytes and microglial cells. Increased IL-6 levels caused by traumatic brain injury can thus activate STAT3, thereby increasing cell proliferation at the site of injury and resulting in the inhibition of apoptosis. STAT3 can suppress T lymphocytes and decrease the activity of MHC class II molecules on cells of the immune system. Furthermore, the increased levels of IL-6 also impact the blood-brain barrier. Additionally, microglial cells secrete metalloproteinases in the tissues adjacent to the tumor, facilitating its migration and, consequently, facilitating its development. PGE2, which is synthesized by microglial cells during the development of the glioma, suppresses the T lymphocytes and decreases the expression of MHC II molecules. Besides, the generation of reactive oxygen species (ROS) might lead to certain mutations in stem cells that migrate to the injury site. At the site of injury, the risk of mutations and cell proliferation increases, and along with the inhibition of apoptosis, these factors may jointly contribute to carcinogenesis.

Figure 1 Schematic representation of various carcinogenic factors during traumatic brain injury. Traumatic brain injury could lead to the migration of macrophages to the site of injury, followed by increased IL-6 production. Traumatic brain injury also induces enhanced IL-6 secretion by astrocytes and microglial cells. The increased IL-6 could thus activate STAT3, which increases cell proliferation at the site of injury, as well as inhibition of apoptosis. STAT3 suppresses T lymphocytes and inhibits major histocompatibility complex (MHC) class II molecules on cells of the immune system. The increased IL-6 also damages the blood-brain barrier (BBB). In addition, microglia secretes metalloproteinases in the tissues adjacent to the tumor, facilitating its migration and development. PGE2 is also synthesized by microglia and suppress T lymphocytes, and also decrease the expression of MHC II molecules on antigen-presenting cells. Besides, reactive oxygen species (ROS) might lead to certain mutations in stem cells that migrate to the site of injury. At the site of injury, the risk of these mutations, and cell proliferation increase, as well as the apoptosis inhibition, may jointly contribute to carcinogenesis.

Inflammation at the site of traumatic brain injury and glioma has been well documented in the literature.63,64 Besides, ROS, the major contributor of oxidative stress, are metabolic byproducts originating from different sources in hypoxic65 conditions and exhibit condition-dependent functions.66,67 The activation of inflammation and oxidative stress are reported in both traumatic brain injury and glioma, and both conditions appear to share a common network of signaling for downstream functions (Figure 2). Interestingly, the activation of inflammation can also contribute to oncogenesis via the generation of ROS and the activation of oxidative stress,68 and conversely, oxidative stress also promotes inflammation.69 Specifically, in this situation, astrocytes, microglia, stem cells, and even neurons can be stimulated to increase ROS and RNS (NO, ONOO),7072 which participate in regulating inflammation and oxidative stress in traumatic brain injury and glioma.

Figure 2 Common inflammatory and oxidative stress-related signaling pathways for traumatic brain injury and glioma. Activation of inflammation and oxidative stress are reported in both traumatic brain injury and glioma, and both conditions share a common network of signaling for downstream functions. Specifically, in the cases of oxidative stress or inflammation in the brain, more ROS could thus be generated. Several cancer-specific external stimuli like the TNF-, could lead to a decrease in the mitochondrial membrane potential that activates ROS generation. Besides, the NADPH oxidase (NOXs) family proteins are one of the main producers of ROS in various cancers, as well as in traumatic brain injuries. And specific signals like TGF-, MAPK, AKT, ERK and various others, could lead to conformational changes in the NOX complex and increase ROS generation. Another important pathway that acts on glioma and traumatic brain injury in a similar manner is hypoxia-inducing factor 1 (HIF-1), which could be upregulated due to the inhibition of degradation via PHD inactivation. HIF-1 could increase the expression of glucose transporter 3 (GLUT3), erythropoietin (EPO), VEGF, as well as BNIP3. Besides, nuclear factor-B (NF-B) can increase the production of ROS, which can also be regulated by the Ras-Raf-MEK pathway via regulating GATA-6. Transcriptional enhancement of HSF1 by Ras could activate the SESN1 and SESN3 genes to promote the production of ROS. TGF also increases the production of ROS through activating GSK3 and mTOR signaling pathways in mitochondria, as well as inhibiting antioxidant enzymes, like the SOD and glutathione peroxidase (GPx).

After traumatic brain injury, there is sequential migration of the resident microglia and myeloid inflammatory cells to the site of injury.73 These inflammatory cells contribute to oncogenesis via promoting ROS generation, which has mutagenic properties, or via the secretion of cytokines and growth factors, in addition to maintaining an inflammatory response.68 During oxidative stress or inflammation in the brain, there is an increase in ROS could generation in the mitochondria.7476 Several cancer-specific external stimuli, including TNF-, lead to a decrease in the mitochondrial membrane potential and interfere with the components of the electron transport chain (ETC), thereby promoting ROS generation.77,78 Besides, the NADPH oxidase (NOXs) protein family is one of the main producers of ROS in various cancers and traumatic brain injuries.79 Moreover, specific markers, such as TGF-, MAPK, AKT, and ERK, among others,80,81 can lead to conformational changes in the NOX complex and increase ROS generation.82 Another indispensable pathway that has an impact on glioma and traumatic brain injury is hypoxia-inducing factor 1 (HIF-1), which can be upregulated owing to the inhibition of degradation via the inactivation of PHD.83,84 HIF-1 increases the expression of glucose transporter 3 (GLUT3), erythropoietin (EPO), VEGF, and BNIP3.8588 Several other signaling pathways are involved in the activation of inflammation and oxidative stress. Nuclear factor-B (NF-B) can increase ROS generation via a positive feedback loop of TNF regulation.89 Additionally, ROS can be regulated by the Ras-Raf-MEK pathway through the transcriptional regulation of GATA-6.90,91 It has been reported that transcriptional enhancement of HSF1 by Ras upregulates SESN1 and SESN3 genes to promote ROS production.92 Besides, TGF also increases the production of ROS by activating the GSK3 and mTOR signaling pathways in the mitochondria and inhibiting antioxidant enzymes, including SOD and glutathione peroxidase (GPx) (Figure 2).93,94

Following a traumatic brain injury, there is an increase in free radicals and the expression of several pro-inflammatory genes by various transcription factors such as NF-B.95,96 This knowledge could be used in anticancer drug discovery. ROS levels increased by oxidation therapy can trigger cell death via necrosis or apoptosis.97 Flavonoids, such as quercetin,98,99 catechins,100 and proanthocyanins,101,102 protect glial cells from inflammation and oxidative stress. These compounds exert protective effects in the brains of patients with cancer and help prevent traumatic brain injury. An anticancer agent, gallic acid, is not only toxic to glioma cells but also exerts beneficial effects in the recovery from traumatic brain injuries.103105 Cardamonin (a chalcone) is effective as an anti-inflammatory and anti-carcinogenic agent in glioma.106,107 Hyperbaric oxygen (HBO) therapy is a recently developed method108 that has been extensively used as an adjuvant in the treatment of various diseases predominantly related to hypoxic conditions. As traumatic brain injury and glioma are related to hypoxia, HBO therapy may be expected to be efficacious in the management of these diseases.109111 However, there could be significant differences in outcomes among patients, depending on the size of the lesion, tumor type, and malignancy.112114 Besides, several drugs, including glycyrrhizin,115 salidroside,116118 and astragaloside,119,120 may be used in both glioma and traumatic brain injury treatment due to the counteracting effect of common signaling pathways (Figure 3).

Figure 3 Selected common therapeutic approaches applied for both glioma and traumatic brain injury. An anticancer agent, gallic acid, could be of great toxic effects on glioma cells, and together exerts beneficial effects on recovery of traumatic brain injuries. Cardamonin (a chalcone) indicates effective anti-inflammatory and anti-carcinogenic activity in glioma. Hyperbaric oxygen (HBO) therapy is a recently developed method that has been extensively used as an adjunctive treatment for various diseases predominantly related to hypoxic conditions, and could be effective for treatment of both glioma and traumatic brain injury. Besides, several other kinds of drugs, like the glycyrrhizin, salidroside and astragaloside, could be used in both glioma and traumatic brain injury treatment due to the counteracting effect of common signaling pathways. Several flavonoids such as quercetin, catechins, and proanthocyanins also protect the glial cells from inflammation and oxidative stress, and could be potentially effective for treatment of these two diseases.

Currently, comprehensive research establishing the relationship between the mechanisms of traumatic brain injury and tumorigenesis is necessary. However, there could be some obstacles. First, the considerable time interval between brain injury and the onset of glioma poses a challenge to perform in vivo studies. Secondly, designing in vitro studies using primary cultures can also be difficult owing to a large number of different types of cells that constitute the brain tissue. The use of immortalized glial cell lines is also excluded owing to their physiological dissimilarity with normal brain cells. Therefore, more efforts should be directed toward establishing suitable in vivo and in vitro models to explore the causal relationship between traumatic brain injury and glioma.

The possible association between traumatic brain injury and glioma should be further examined by designing additional experimental and clinical research. Much more additional factors may be involved in the formation of the post-traumatic glioma. These factors might have been unintentionally omitted during the selection of study groups in various previous studies, leading to the result of the lack of connection between injury and glioma, which is why further explorations on the etiology of post-traumatic glioma are urgently needed. Besides, it may be more difficult to effectively treat patients who suffer from both glioma and traumatic brain injury compared to those with traumatic brain injury without glioma. The survival rate of patients with glioma is bound to increase with the development of anticancer drugs, including those suggested in this review. Treating traumatic brain injury in patients with glioma can be still challenging and requires specific treatment modalities. Thus, the development of effective strategies in the management of traumatic brain injury in patients with glioma is essential.

The authors warrant that the article and all figures included in this work are the authors original work and has not been published before.

The authors declare no competing financial interests and no conflicts of interest for this work.

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